Benzoylguanidine salt and hydrates thereof

ABSTRACT

4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidine hydrochloride and its hydrates, processes for preparing this benzoylguanidine salt and its hydrates, pharmaceutical compositions containing this benzoylguanidine salt and its hydrates, and its use in treating diseases, particularly those in which inhibition of the cellular Na + /H +  exchange is of therapeutic benefit.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/731,825, filedDec. 9, 2003, which application is a continuation of U.S. Ser. No.10/057,597, filed Jan. 25, 2002, which claims priority to U.S. Ser. No.60/281,344, filed Apr. 4, 2001, and German Patent Application No. 101 06970.7 filed Feb. 15, 2001, each of which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to the hydrochloride of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidine,processes for preparing it and its use in preparing a pharmaceuticalcomposition.

BACKGROUND OF THE INVENTION

A number of benzoylguanidine derivatives are known in the art. Thus, forexample, International Patent Application WO 00/17176 disclosesbenzoylguanidine derivatives which are characterized by valuablepharmacological properties. These compounds are effective againstarrhythmias which occur in hypoxia, for example. They may also be usedfor complaints connected with ischaemia (such as cardiac, cerebral,gastrointestinal (such as mesenteric thrombosis/embolism), pulmonary orrenal ischaemia, ischaemia of the liver, and ischaemia of the skeletalmuscles). Corresponding indications include, for example, coronary heartdisease, cardiac infarct, angina pectoris, stable angina pectoris,ventricular arrhythmia, subventricular arrhythmias, cardiacinsufficiency, and also for assisting bypass operations, for assistingopen heart surgery, for assisting operations which require aninterruption to the blood supply to the heart and to assist in hearttransplants, embolism in the pulmonary circulation, acute or chronickidney failure, chronic renal insufficiency, cerebral infarct,reperfusion damage in the restoration of blood supply to areas of thebrain after the break-up of vascular occlusions, and acute and chroniccirculatory disorders of the brain. The abovementioned compounds mayalso be used in such cases in conjunction with thrombolytic agents suchas t-PA, streptokinase, and urokinase.

During reperfusion of the ischemic heart (e.g., after an attack ofangina pectoris or a cardiac infarct) irreversible damage may occur tocardiomyocytes in the affected region. In such cases the compounds havea cardioprotective effect, inter alia.

The category of ischaemia should also include the prevention of damageto transplants (e.g., as protection for the transplanted organ, such as,for example, liver, kidney, heart, or lung, before, during, and afterimplantation and during the storage of the transplant organs), which mayoccur in connection with transplantation. The compounds disclosed in WO00/17176 are also pharmaceutical compositions with a protective effectin carrying out angioplastic surgical interventions on the heart and onperipheral blood vessels.

In essential hypertension and diabetic nephropathy the cellularsodium-proton exchange is increased. The compounds are thereforesuitable as inhibitors of this exchange for the preventive treatment ofthese diseases.

The compounds are further characterized by a powerful inhibiting effecton the proliferation of cells. Therefore, the compounds are useful asmedicaments in diseases where cell proliferation plays a primary orsecondary part and may be used as agents against cancers, benign tumorsor, for example, prostatic hypertrophy, atherosclerosis, organhypertrophy and hyperplasia, fibrotic diseases, and late complicationsof diabetes.

The abovementioned pharmacologically valuable properties of thebenzoylguanidine derivatives disclosed in the prior art are the mainprerequisite for effective use of a compound as a pharmaceuticalcomposition. An active substance, however, has to satisfy still morerequirements in order to be allowed to be used as a medicament. Theseparameters are largely connected to the physico-chemical nature of theactive substance.

Without being restricted thereto, examples of these parameters are thestability of effect of the starting substance under different ambientconditions, stability during the production of the pharmaceuticalformulation, and stability in the finished compositions of themedicament. The pharmaceutical active substance used to prepare thepharmaceutical compositions should therefore have high stability whichmust also be guaranteed even under different ambient conditions. This isabsolutely necessary to prevent the use of pharmaceutical compositionswhich contain breakdown products of the active substance, for example,in addition to the active substance itself. In such a case, the contentof active substance present in pharmaceutical formulations may be lowerthan specified.

The absorption of moisture reduces the content of pharmaceutical activesubstance because of the increase in weight due to the uptake of water.Pharmaceutical compositions with a tendency to absorb moisture have tobe protected from moisture during storage, for example, by the additionof suitable drying agents or by storing the pharmaceutical compositionin an environment which is protected from damp. Moreover, the uptake ofmoisture may reduce the content of pharmaceutical active substanceduring manufacture if the pharmaceutical composition is exposed to theenvironment without any protection from moisture whatsoever. Preferably,therefore, a pharmaceutical active substance should be only slightlyhygroscopic.

As the crystal modification of an active substance can influence theactivity of a pharmaceutical composition, it is necessary to clarify anyexisting polymorphism of an active substance present in crystalline formas much as possible. If there are different polymorphic modifications ofan active substance, care must be taken to ensure that the crystallinemodification of the substance does not change in the subsequentpharmaceutical preparation. Otherwise, this could have a detrimentaleffect on the reproducible activity of the medicament. In this context,active substances which are characterized by limited polymorphism arepreferred.

Another criterion which may be of exceptional importance in certaincircumstances, depending on the choice of formulation or on the choiceof the method of production of the formulation, is the solubility of theactive substance. If, for example, pharmaceutical solutions are prepared(for example for infusions), it is essential that the active substanceis sufficiently soluble in physiologically acceptable solvents. Asufficiently soluble active substance is also very important forpharmaceutical compositions administered orally.

The underlying aim of the present invention is to prepare apharmaceutical active substance which is not only characterized by apotent pharmacological activity but also satisfies as far as possiblethe physico-chemical requirements referred to above.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that the abovementioned aim is achieved by means ofthe compound4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride 1

The compound of formula 1 is not hygroscopic and dissolves readily inphysiologically acceptable solvents. It is also characterized by a highdegree of stability.

The methanesulfonate of formula 1′ disclosed in WO 00/17176

unlike the compound of formula 1, does not meet the requirements set outhereinbefore, however.

Accordingly, in one aspect, the present invention relates to thecompound of formula 1 as such. In another aspect, the present inventionrelates to the compound of formula 1 in the form of its hydrates,preferably in the form of its monohydrate or hemihydrate.

In another aspect, the present invention relates to the use of thecompound of formula 1 as a medicament. The present invention furtherrelates to the use of the compound of formula 1, optionally in the formof its hydrates, for preparing a pharmaceutical composition for treatingdiseases in which inhibitors of the cellular Na⁺/H⁺ exchange may developa therapeutic benefit.

The present invention further relates to the use of the compound offormula 1 to prepare a pharmaceutical composition for treatingcardiovascular diseases.

The present invention further relates to the use of the compound offormula 1 to prepare a pharmaceutical composition for treatingarrhythmia such as occurs in hypoxia, for example. The present inventionfurther relates to the use of the compound of formula 1 to prepare apharmaceutical composition for treating complaints connected withischaemia (such as: cardiac, cerebral, gastrointestinal (such asmesenteric thrombosis/embolism), pulmonary, renal ischaemia, ischaemiaof the liver, and ischaemia of the skeletal muscles. The presentinvention further relates to the use of the compound of formula 1 toprepare a pharmaceutical composition for treating diseases selected fromthe group consisting of coronary heart disease, cardiac infarct, anginapectoris, stable angina pectoris, ventricular arrhythmia, subventriculararrhythmias, cardiac insufficiency, and also for assisting bypassoperations, for assisting open heart surgery, for assisting operationswhich require an interruption to the blood supply to the heart and toassist in heart transplants, embolism in the pulmonary circulation,acute or chronic kidney failure, chronic renal insufficiency, cerebralinfarct, reperfusion damage in the restoration of blood supply to areasof the brain after the dissolving of vascular occlusions and acute, andchronic circulatory disorders of the brain. The present inventionfurther relates to the use of the compound of formula 1 to prepare apharmaceutical composition for treating diseases in which the use ofcardioprotective active substances may be of therapeutic benefit. Thepresent invention further relates to the use of the compound of formula1 to prepare a pharmaceutical composition for treating cancers, benigntumors or, for example, prostatic hypertrophy, atherosclerosis, organhypertrophy and hyperplasia, fibrotic diseases, and late complicationsof diabetes.

The compound of formula 1 may be used as an aqueous injectable solution(e.g., for intravenous, intramuscular, or subcutaneous administration),as a tablet, as a suppository, as an ointment, as a plaster fortransdermal administration, as an aerosol for inhalation into the lungsor as a nasal spray.

The content of active substance in a tablet or a suppository is between5 mg and 200 mg, preferably between 10 mg and 50 mg. For inhalation, thesingle dose is between 0.05 mg and 20 mg, preferably between 0.2 mg and5 mg. For parenteral injection, the single dose is between 0.1 mg and 50mg, preferably between 0.5 mg and 20 mg. The doses specified above maybe given several times a day if necessary.

The following are some examples of pharmaceutical preparationscontaining the active substance: TABLETS Component Amount (mg) Compoundof formula 1 18.0 magnesium stearate  1.2 maize starch 60.0 lactose 90.0polyvinylpyrrolidone  1.5 SOLUTION FOR INJECTION Component AmountCompound of formula 1 0.3 g sodium chloride 0.9 g water for injectionsad 100 mL

This solution can be sterilized using standard methods.

WO 00/17176 discloses possible methods of production which can be usedto synthesize the free base4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidine.Starting from this compound, the following possible methods ofsynthesizing the compound of formula 1 are illustrated by way ofexample.

EXAMPLE 14-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride

15.1 g of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidineis taken up in 151 mL of methanol and the resulting suspension is cooledto about 10° C. 16 mL of a saturated ethereal HCl solution are added tothis suspension which is thus acidified to a pH of between 1 and 2.Stirring is continued, while cooling with ice, until crystallization iscomplete. The crystals are suction filtered, washed with cold methanol,and then with cold diethyl ether. Yield: 16.19 g; melting point: 223° C.(uncorrected).

EXAMPLE 24-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride hemihydrate

15.0 kg of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidineis taken and combined with 120 L of ethyl acetate. The suspension isheated to about 45° C. and combined with 30 L of water. The resultingmixture is stirred for about 15 minutes and the aqueous phase is thenseparated off. A solution of 3.62 kg of concentrated hydrochloric acidin 20 L of water is added to the organic phase at a constanttemperature. Within about 1 to 2 hours, the mixture is cooled to 25° C.to 20° C. The hydrochloride obtained is separated off, washed with 50 Lof ethyl acetate, and dried in vacuo at about 60° C. Yield: 78%; meltingpoint: 225° C.±5° C. (DSC at a heating rate of 10 K/min).

EXAMPLE 34-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride monohydrate

109.4 g of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidineis suspended in 1.5 L of water and heated to about 50° C. 26.1 mL ofconcentrated aqueous hydrochloric acid is diluted with 300 mL of waterand added dropwise to the preheated suspension within about 20 minutes.The mixture is stirred for about 15 minutes at constant temperature.Then the temperature is lowered to about 35° C. with stirring over aperiod of about 1.5 hours. It is then cooled to 5° C. to 10° C. andstirred for another hour at this temperature. The crystals obtained areseparated off, washed with a little water, and dried in vacuo at about50° C. Yield: 116.5 g; melting point: 180° C.±5° C. (DSC at a heatingrate of 10 K/min).

1.4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride 1


2. A pharmaceutical composition comprising: (a) the compound accordingto claim 1; and (b) a pharmaceutically acceptable excipient.
 3. A methodof treating diseases in which inhibition of the cellular Na⁺/H⁺ exchangeis of therapeutic benefit in a patient in need thereof, the methodcomprising administering to the patient an effective amount of thecompound according to claim
 1. 4. The method according to claim 3,wherein the compound according to claim 1 is administered in the form ofan aqueous injectable solution, a tablet, a suppository, an ointment, atransdermal plaster, an inhalation aerosol, or a nasal spray.
 5. Amethod of treating diseases in which inhibition of the cellular Na⁺/H⁺exchange is of therapeutic benefit in a patient in need thereof, themethod comprising administering to the patient an effective amount of ahydrate of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride 1


6. A method of treating diseases in which inhibition of the cellularNa⁺/H⁺ exchange is of therapeutic benefit in a patient in need thereof,the method comprising administering to the patient an effective amountof a monohydrate of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride 1


7. A method of treating diseases in which inhibition of the cellularNa⁺/H⁺ exchange is of therapeutic benefit in a patient in need thereof,the method comprising administering to the patient an effective amountof a hemihydrate of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride 1


8. The method according to claim 5, wherein the a hydrate of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride 1 is administered in the form of an aqueous injectablesolution, a tablet, a suppository, an ointment, a transdermal plaster,an inhalation aerosol, or a nasal spray.
 9. The method according toclaim 6, wherein the monohydrate of4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride 1 is administered in the form of an aqueous injectablesolution, a tablet, a suppository, an ointment, a transdermal plaster,an inhalation aerosol, or a nasal spray.
 10. The method according toclaim 7, wherein the4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidinehydrochloride 1 is administered in the form of an aqueous injectablesolution, a tablet, a suppository, an ointment, a transdermal plaster,an inhalation aerosol, or a nasal spray.